Charcot–Marie–Tooth disease (CMT) refers to a group of genetically heterogeneous disorders affecting peripheral nerve function.

Charcot–Marie–Tooth disease (CMT)

Definition:

• Charcot–Marie–Tooth disease (CMT) refers to a group of genetically heterogeneous disorders affecting peripheral nerve function.
• Named after Jean-Martin Charcot, Pierre Marie, and Henry Tooth, who described the disorder in 1886.

Epidemiology

• Prevalence:
  • Most common inherited neuromuscular disorder.
  • Affects approximately 1 in 2500 individuals (Skre 1974).
• Childhood Impact:
  • Accounts for ~40% of childhood chronic neuropathies.

Pathophysiology

• Nature of Disease:
  • Characterized by degeneration of:
    • Axon.
    • Myelin sheath.
    • Or both.
• Resulting Symptoms:
  • Progressive, symmetrical distal weakness.
  • Sensory loss.
  • Areflexia (loss of reflexes).

Genetic Basis

• Causative Mechanisms:
  • Disorders of genes affecting:
    • Myelin compaction and maintenance.
    • Cytoskeletal formation.
    • Axonal transport.
    • Mitochondrial metabolism.
• Inheritance Patterns:
  • Autosomal dominant.
  • Autosomal recessive.
  • X-linked.
  • Mitochondrial.

Classic Phenotype

• Core Symptoms:
  • Gait difficulties.
  • Foot deformity (e.g., pes cavus or pes planus with valgus deviation).
  • Sensory loss.
  • Wasting of distal muscles in hands and feet.
• Progression:
  • Symptoms typically begin distally and in lower limbs before progressing to upper limbs.
  • Slow progression often delays medical attention.
• Onset:
  • Highly variable: from birth to the sixth/seventh decades.
  • Most commonly presents in the first two decades of life.
• Axonal Degeneration:
  • Affects longest fibres first, correlating with weakness severity.

Clinical Presentation in Children

• Gait Disturbances:
  • High-stepping gait.
  • Difficulties running.
  • Frequent falls or unsteadiness.
• Foot Deformities:
  • Pes cavus (high-arched foot) with hammer toes:
    • Imbalance between long flexors and invertors of the ankle.
    • Involvement of intrinsic foot muscles may be critical.
  • Pes planus (flatfoot) with marked valgus deviation.
• Muscle Atrophy:
  • Symmetrical atrophy of peroneal muscles:
    • Later involves calves and lower thighs.
  • Upper limb involvement:
    • Atrophy and weakness of small hand muscles (claw hand – main en griffe).
• Tendon Reflexes:
  • Decreased or absent.

Sensory Involvement

• Loss of Sensation:
  • Abnormalities of touch, proprioception, and vibration.
  • Sensory ataxia.
• Pain:
  • Dysaesthesiae or shooting pains are not typical.
  • Severe pain may result from foot deformities or calluses.

Associated Symptoms

• Vasomotor Disturbances:
  • Frequent cyanosis and marbling of the skin.
• Muscle Cramps:
  • Commonly reported.
• Other Considerations:
  • Symptoms are generally symmetrical.

Key Points for Examination

• Look for signs of distal muscle atrophy and foot deformities.
• Assess sensory loss patterns and tendon reflexes.
• Document gait disturbances and upper limb involvement (e.g., claw hand).

Overview of Classification

• Terminology:
  • CMT is also referred to as hereditary motor and sensory neuropathy (HMSN).
  • Specific types:
    • Hereditary sensory neuropathy (HSN): Predominantly affects sensory fibers.
    • Hereditary motor neuropathy (HMN): Predominantly affects motor fibers.
• Classification Basis:
  • Neurophysiological and histopathological characteristics.
  • Mode of inheritance.
  • Genetic testing informed by phenotypic clues and conduction velocities.

Advances in Genetic Testing

• Next-generation sequencing:
  • Whole-exome and whole-genome sequencing.
  • Disease-specific gene panels.
• Impact:
  • Improved classification and diagnosis.
  • Identification of significant phenotypic and genotypic overlaps between CMT types.

Traditional Classification

1. CMT1 (Demyelinating CMT):

   • Motor conduction velocity (MCV): < 38 m/s in adults.
   • Subtype CMT1A:
     • Most common demyelinating disorder (70% of cases).
     • Genetic cause:
       • Duplication of the PMP22 gene on chromosome 17p11.2.
       • Results in overexpression of peripheral myelin protein 22.
       • Often caused by unequal crossing-over during meiosis.
     • Clinical features:
       • Onset in the first decade, though neonatal onset possible.
       • Weakness, sensory loss, calf hypertrophy, scoliosis, and tremor.
       • Slow progression; most remain ambulant.
       • Exacerbations: Pregnancy, rapid growth, infections, or exposure to vincristine.
       • Rare response to steroid treatment in specific cases.
     • Diagnostic markers:
       • Elevated CSF protein in over half of cases.
       • Nerve enlargement detected via ultrasound neurography.
   • CMT1B-F: Other subtypes linked to mutations in different myelin-related genes.

2. CMT2 (Axonal CMT):

   • MCV: > 38 m/s in adults.
   • Characterized by axonal degeneration rather than demyelination.

3. CMT4 (Autosomal Recessive Demyelinating CMT):

   • Rare subtype with severe presentations and early onset.

4. CMT3 (Déjerine–Sottas Neuropathy):

   • Severe early-onset form of demyelinating neuropathy.
   • Features:
     • Delayed motor milestones.
     • Hypomyelination on nerve biopsy.
     • Linked to point mutations in genes causing CMT1.

5. Intermediate CMT:

   • MCV range: 25–45 m/s.
   • Features between CMT1 and CMT2.

Proposed New Nomenclature

• Attributes:
  • Includes conduction velocity (demyelinating [de], axonal [ax], or intermediate [int]).
  • Inheritance pattern.
  • Causative gene, if known.
• Example:
  • Autosomal dominant demyelinating CMT due to PMP22 duplication: CMT-de/AD/PMP22.

CMT1/HMSN1

• Prevalence:
  • Represents 3.8 per 100,000 population.
  • Accounts for ~50% of pediatric hereditary neuropathies.
  • CMT1 is genetically heterogeneous but more than 80% of childhood cases are linked to chromosome 17 (CMT1A).
• Clinical Features:
  • Gradual progression, often stable over long periods.
  • Common complications:
    • Scoliosis, hip dysplasia, metatarsal stress fractures.
    • Calf hypertrophy, clumsiness, and tremors.
  • Early signs:
    • Loss of deep tendon reflexes, especially ankle jerks.
• Management:
  • Avoid vincristine and monitor during pregnancy.
  • Rare steroid-responsive cases documented.

Phenotypic and Genotypic Variability

• Significant overlap among subtypes.
• As genetic understanding evolves, classification systems are expected to become more standardized.

Key Diagnostic Features

• Clinical Characteristics:
  • Sensory deficits are critical for distinguishing CMT1 from distal myopathies or spinal amyotrophy.
  • Progressive distal weakness, sensory loss, and decreased reflexes are typical.
  • Significant variability in clinical expression; some individuals remain asymptomatic.
• Electrophysiology:
  • Nerve Conduction Studies (NCS):
    • Motor and sensory nerve conduction velocities (NCV) < 60% of the lower limit of normal.
    • Increased distal latencies may precede slowing of NCV.
    • Early abnormalities detectable in most children with CMT1A by age 3.
    • Carrier parents often have abnormal NCVs even if asymptomatic.
  • Electromyography (EMG):
    • Neurogenic changes are mild to moderate.

Genetic Diagnosis

• Common Genetic Testing:
  • Testing for chromosome 17p11.2 duplication (PMP22 gene duplication) confirms diagnosis in most cases.
  • Further Genetic Testing:
    • Sequence MPZ (myelin protein zero) and PMP22 if duplication testing is negative.
    • Utilize neuropathy-specific gene panels for broader genetic analysis.
• Associated Genes:
  • CMT1A: PMP22 duplication or point mutations.
  • CMT1B: MPZ mutations (associated with variable phenotypes, including CMT1-like, late-onset axonal forms, or intermediate forms).
  • CMT1C: LITAF/SIMPLE mutations (protein degradation defect).
  • CMT1D: EGR2 mutations (transcription factor regulating myelin-related genes).
  • CMT4E: Severe autosomal recessive forms caused by homozygous EGR2 mutations.

Phenotypic Variability

• Manifestations:
  • Most children with CMT1A show signs by age 3, but mild and asymptomatic cases exist.
  • Systematic examination of family members improves diagnostic yield.
  • Associated features:
    • Deafness (PMP22, MPZ mutations).
    • Pupillary abnormalities (MPZ mutations).
• Mouse and Rat Models:
  • Overexpression of PMP22 replicates CMT1A features.
  • Severity correlates with PMP22 expression levels.

Role of Nerve Biopsy

• Indications:
  • Rarely necessary, especially if a family history or genetic diagnosis is established.
  • Main utility:
    • Differentiate from chronic inflammatory neuropathies.
    • Trial of steroid treatment may follow in specific cases.
• Findings:
  • Hypomyelination or demyelination in severe cases.

Challenges in Diagnosis

• Overlap with Other CMT Subtypes:
  • MPZ mutations may present as CMT1, late-onset CMT2, or intermediate forms.
• Mild Cases:
  • Clinical and nerve biopsy findings may be minimal, especially in young children.

Emerging Mechanistic Insights

• PMP22:
  • Comprises 2–5% of peripheral myelin.
  • Overexpression disrupts cellular trafficking, contributing to neuropathy.
• MPZ:
  • Constitutes ~50% of myelin protein.
  • Essential for myelin adhesion.
• LITAF/SIMPLE:
  • Implicated in protein degradation pathways.
• EGR2:
  • Regulates multiple myelin-related genes.

Summary

• Diagnosis of CMT1 combines clinical evaluation, nerve conduction studies, and genetic testing.
• PMP22 duplication is the most common genetic cause.
• Advances in genetic testing, including neuropathy-specific panels, are improving diagnostic precision.
• Nerve biopsy is now rarely required, with genetic testing offering non-invasive diagnostic alternatives.
• Systematic evaluation of family members enhances diagnostic accuracy, especially in mild or asymptomatic cases.

CMT1 Pathology

• Nerve and Muscle Biopsy Findings:
  • Segmental Demyelination and Remyelination:
    • Leads to formation of onion bulbs:
      • Composed of Schwann cells and their processes.
      • Seen under electron microscopy.
  • Reduction in Myelinated Fibres:
    • Greatest loss among large-calibre fibers.
    • Distribution of fibre diameters becomes unimodal.
  • Unmyelinated Fibres:
    • Typically unaffected.
• Additional Observations:
  • Segmental and paranodal demyelination/remyelination, particularly in distal nerves.
  • Hypertrophy of nerve roots and plexuses in severe cases.
  • Muscle degeneration is secondary to neural damage.
• Subtype-Specific Features:
  • CMT1A (PMP22 mutations):
    • Classic pathological findings as described above.
  • CMT1B (MPZ mutations):
    • Similar features to CMT1A.
    • Additional findings:
      • Uncompacted myelin in some fibres.
      • Focal folding of myelin (tomacula).

X-Linked CMT (CMTX)

• Overview:
  • Accounts for ~10% of adult CMT cases.
  • Most common form: CMTX1, caused by mutations in the GJB1 (Cx32) gene.
    • Encodes connexin 32, a gap junction protein located near nodes of Ranvier and Schmidt–Lanterman incisures.
• Pathological Features:
  • Combination of demyelination and axonal degeneration:
    • Moderate loss of myelinated fibres.
    • Lesions vary, but chronic de- and re-myelination are common.
• Clinical-Pathological Variability:
  • Male patients:
    • Often more severely affected than females.
    • Intermediate conduction velocities (~31 m/s mean peroneal MCV in males vs. ~22 m/s in CMT1A males).
  • Female patients:
    • Milder clinical involvement.
    • Conduction velocities often in the axonal range.
• Additional Syndromic X-Linked Neuropathies:
  • CMTX2, CMTX4, CMTX5, and others:
    • Often associated with intellectual disability and syndromic features.
    • May not be classified strictly as CMT.

Unique Findings in X-Linked CMT

• Neurological and Systemic Features:
  • Some cases present with isolated deafness.
  • Transient CNS symptoms associated with white matter lesions.
• Genetic Variability:
  • Other X-linked loci (e.g., CMTX3, CMTX6) linked to structural genetic changes or mutations in specific genes (e.g., PDK3).

Autosomal Recessive Demyelinating Types of Charcot–Marie–Tooth (CMT4)

• Definition:
  • CMT4 refers to a group of severe, early-onset autosomal recessive demyelinating neuropathies.
• Key Features:
  • Slow motor conduction velocities (typically ~20 m/s; range: 3–37 m/s).
  • Affected children may have similarly affected siblings and unaffected parents, often related (consanguinity).
  • Higher prevalence in North African and Middle Eastern populations.

Subtypes of CMT4

1. CMT4A:

   • Gene: GDAP1 (involved in mitochondrial fission).
   • Clinical Features:
     • Early-onset severe phenotype.
     • Prominent foot deformities (e.g., pes cavus).
     • Progressive weakness and sensory loss, starting in lower limbs and progressing to upper limbs.
     • Loss of ambulation by the second or third decade.
     • May involve laryngeal and diaphragmatic paralysis in later life.
   • Histopathology:
     • Demyelinating or axonal changes depending on the kindred.

2. CMT4B1 and CMT4B2:

   • Genes: MTMR2 (CMT4B1) and SBF2/MTMR13 (CMT4B2).
   • Clinical Features:
     • Early distal weakness progressing to proximal weakness.
     • Pes cavus, ptosis, ophthalmoplegia, and facial nerve weakness.
     • Dysphagia, vocal cord paresis, scoliosis, and nocturnal hypoventilation.
     • CMT4B2 often associated with congenital or juvenile glaucoma.
   • Histopathology:
     • Striking in- and out-foldings of myelin.
     • Myelin outfoldings also seen in MPZ, PRX, and FGD4 mutations.

3. CMT4C:

   • Gene: SH3TC2 (regulates endosomal recycling).
   • Clinical Features:
     • Early-onset scoliosis, often predating neuropathy.
     • Onset usually in the first decade, with variability in progression.
     • Ambulation may persist into the fifth decade or wheelchair dependence in adolescence.
   • Histopathology:
     • Basal lamina onion bulbs and Schwann cell processes around unmyelinated fibres.
     • Giant axons.

4. CMT4D (HMSN-Lom):

   • Gene: NDRG1 (important for Schwann cell trafficking and endosomal transport).
   • Population: Predominantly seen in Roma (Gypsy) populations.
   • Clinical Features:
     • Similar to other autosomal recessive demyelinating neuropathies.
     • Progressive deafness after the first decade.

5. CMT4E:

   • Gene: EGR2 (early growth response 2).
   • Clinical Features:
     • Severe phenotypes such as Déjerine–Sottas or congenital hypomyelinating neuropathy.
   • Histopathology:
     • Very low nerve conduction velocities (<5 m/s).

6. CMT4F:

   • Gene: PRX (periaxin; crucial for peripheral myelin formation).
   • Clinical Features:
     • Early-onset Déjerine–Sottas phenotype.
     • Prominent sensory involvement with dysaesthesia and ataxia.
   • Histopathology:
     • Severe loss of myelinated fibres, onion bulbs, and myelin outfoldings.

7. CMT4G (HMSN-Russe):

   • Gene: HK1 (hexokinase 1).
   • Population: European Roma.
   • Clinical Features:
     • Slower progression compared to CMT4D.
     • Deafness occurs later.
   • Histopathology:
     • Loss of large myelinated fibres and prominent clusters of regenerated axons.

8. CMT4H:

   • Gene: FGD4 (involved in myelin development and maintenance).
   • Clinical Features:
     • Early-onset sensorimotor neuropathy with slow progression.
     • Remain ambulant into middle age.

9. CMT4J:

   • Gene: Fig4 (involved in intracellular organelle cycling).
   • Clinical Features:
     • Variable onset (childhood to sixth decade).
     • Early proximal weakness, potentially leading to wheelchair dependence by the third decade.
     • Asymmetrical limb involvement and rapid progression in some cases.
   • Histopathology:
     • Combined axonal and demyelinating features.

Epidemiology and Genetic Insights

• CMT4A Prevalence:
  • Constitutes up to 25% of autosomal recessive CMT cases.
• Population Studies:
  • Variability in mutation detection across populations.
  • Common mutations include GDAP1, MTMR2, SH3TC2, NDRG1, and PRX.

Summary

• Autosomal recessive CMT types are severe, early-onset conditions with distinctive clinical and histopathological features.
• Genetic insights have expanded understanding, with subtype-specific genes linked to unique pathological and phenotypic presentations.
• Higher prevalence in consanguineous populations underscores the need for targeted genetic screening and counseling.

Charcot–Marie–Tooth Disease Type 2 (CMT2 / HMSN II)

• Definition:
  • CMT2 is the axonal form of CMT, characterized by degeneration of the axon rather than the myelin sheath.
• Epidemiology:
  • Less frequent in children than CMT1.
  • Accounts for ~20% of childhood CMT cases.
• Inheritance:
  • Both autosomal dominant and autosomal recessive forms have been described.

Clinical Features

• Similarities to CMT1:
  • Distal muscle weakness and atrophy.
  • Sensory loss.
• Differences from CMT1:
  • Later onset, typically in the second or third decade of life.
  • Foot deformity and absent reflexes less common.
  • No nerve hypertrophy or elevated CSF protein.
  • Foot ulcers may occur in subtypes like CMT2B.
  • Upper limb tremors are rare.
• Electrophysiological Characteristics:
  • Normal or mildly reduced motor conduction velocities (>38 m/s in the median nerve).
  • Differentiation from CMT1 is based on nerve conduction studies.

Genetic and Molecular Insights

• Heterogeneity:
  • Linked to at least 22 loci and 20 genes.

1. CMT2A:

   • Gene: MFN2 (mitofusin 2).
   • Role: Involved in mitochondrial fusion and axonal transport.
   • Clinical Features:
     • Early-onset, rapidly progressive in severe cases.
     • Late-onset, slow progression in milder cases.
     • Associated with optic atrophy and vocal cord paresis.
   • Histopathology:
     • Sural nerve biopsy shows axonal degeneration and abnormal mitochondria.

2. CMT2B:

   • Gene: RAB7.
   • Clinical Features:
     • Sensory loss with foot ulcers (resembles HSAN1).
     • Role in axonal transport.

3. CMT2C:

   • Gene: TRPV4.
   • Clinical Features:
     • Diaphragm and vocal cord paralysis.
     • Overlaps with spinal muscular atrophy phenotypes.

4. CMT2D:

   • Gene: GARS (glycyl aminoacyl tRNA synthetase).
   • Clinical Features:
     • Prominent distal upper limb weakness.
     • Can also present as SMA type V.

5. CMT2E:

   • Gene: NEFL (neurofilament light).
   • Clinical Features:
     • Mixed axonal/demyelinating neuropathy.
     • Onset before age 13 in some cases.

6. CMT2L and CMT2F:

   • Genes: HSPB1 (HSP27) and HSPB8 (HSP22).
   • Clinical Features:
     • Adult-onset distal weakness, mild sensory loss, and foot deformity.

7. CMT2I and CMT2J:

   • Gene: MPZ.
   • Clinical Features:
     • Axonal neuropathy with a range of severity.

8. CMT2K:

   • Gene: GDAP1.
   • Clinical Features:
     • Rare, later-onset axonal neuropathy.
     • Allelic to CMT4A.

Pathophysiology

• Axonal Degeneration:
  • Loss of axonal integrity, leading to impaired nerve function.
  • Associated mitochondrial dysfunction in subtypes like CMT2A.
• Molecular Defects:
  • Defects in mitochondrial dynamics, axonal transport, and cytoskeletal integrity.
  • Impairments in amino-acyl tRNA synthetases (e.g., GARS, AARS, YARS).

Histopathology

• Sural Nerve Biopsy:
  • Axonal degeneration with small, rounded mitochondria in MFN2-related neuropathy.
  • Mixed demyelinating/axonal changes in some subtypes.

Key Subtypes and Associations

• CMT2A: Most common, linked to mitochondrial dysfunction.
• CMT2B: Foot ulcers, overlap with HSAN1.
• CMT2C: Respiratory and vocal cord involvement.
• CMT2D: Predominantly upper limb weakness.
• CMT2E-L: Variability in conduction velocities and clinical presentation.

Diagnostic Approach

• Electrophysiology:
  • Nerve conduction studies to distinguish CMT2 from CMT1.
• Genetic Testing:
  • Targeted gene panels based on phenotypic clues.
• Histopathology:
  • Sural nerve biopsy in select cases for confirmation.

Summary

• CMT2 is an axonal neuropathy with significant genetic and clinical heterogeneity.
• Early recognition and genetic testing are critical for diagnosis and subtype identification.
• Advances in molecular biology continue to improve our understanding of this diverse condition.

Autosomal Recessive Forms of CMT2

• Definition:
  • Autosomal recessive forms of CMT2 represent axonal neuropathies with variable phenotypes ranging from classic to severe CMT.
• Key Characteristics:
  • Early onset, often in childhood or early adulthood.
  • Moderate-to-severe motor and sensory impairment.
  • Rare compared to autosomal dominant forms.

Genetic and Molecular Basis

1. CMT2B1:

   • Gene: LMNA (encodes lamin A and C proteins).
   • Role: Intermediate filaments of the inner nuclear membrane.
   • Population:
     • Predominantly reported in Algerian and Moroccan families.
     • Founder effect for the R298C mutation.
   • Phenotype:
     • Onset in childhood to early adulthood.
     • Variable severity and progression rates.
     • Occasionally associated with myopathy in non-North African populations.

2. Recessive Axonal Neuropathy with Neuromyotonia (NMAN):

   • Gene: HINT1 (histidine triad nucleotide-binding protein 1).
   • Phenotype:
     • Motor-predominant neuropathy with childhood onset.
     • Action myotonia and neuromyotonia observed on EMG.

3. Recessive Mitofusin 2 (MFN2) Mutations:

   • Gene: MFN2 (mitochondrial fusion protein).
   • Phenotype:
     • Severe early-onset neuropathy in compound heterozygotes.
     • Mild phenotypes in homozygous mutations.

4. SLC12A6-Associated Neuropathy (Andermann Syndrome):

   • Gene: SLC12A6 (potassium-chloride cotransporter KCC3A).
   • Associated Features:
     • Neuropathy with agenesis of the corpus callosum.
     • Described initially in French Canadians.

5. Other Autosomal Recessive Axonal Neuropathies:

   • Giant Axonal Neuropathy: Includes central nervous system involvement.
   • SMARD1 (Severe Infantile Axonal Neuropathy with Respiratory Failure):
     • Overlaps with spinal muscular atrophy.
     • Includes significant sensory and respiratory deficits.

Pathology of Autosomal Recessive CMT2

• General Pathological Features:

  • Axonal degeneration with secondary involvement of myelin.
  • Loss of myelinated fibers, particularly large-caliber axons.
  • Presence of regenerative clusters.
  • Onion Bulbs: Rare.
  • Internodes: Shortened and irregular in length.

• Distinctive Histological Observations:

  • Acute axonal lesions are rare.
  • Pathological abnormalities may be subtle, requiring detailed evaluation.

Clinical Presentation

• Common Features:

  • Distal muscle weakness and atrophy.
  • Sensory deficits.
  • Loss of reflexes.
  • Progression to paralysis below knees and elbows in severe cases.

• Subtypes:

  • CMT2B1: Early-to-moderate progression, occasional myopathy.
  • NMAN: Neuromyotonia, motor-predominant phenotype.
  • Andermann Syndrome: Neuropathy with central nervous system features.

Diagnostic Insights

• Electrophysiological Studies:

  • Motor conduction velocities generally >35 m/s.
  • EMG may reveal action myotonia in HINT1-related NMAN.

• Genetic Testing:

  • Confirmatory genetic diagnosis for LMNA, HINT1, MFN2, and other associated genes.
  • Targeted testing in populations with a known founder effect (e.g., North Africa).

• Histopathology:

  • Nerve biopsies show characteristic axonal degeneration with variable secondary features.

Summary

• Autosomal recessive forms of CMT2 encompass a diverse group of axonal neuropathies with unique genetic and clinical characteristics.
• Early recognition through genetic and electrophysiological evaluation is essential for accurate diagnosis and management.
• Advances in understanding mitochondrial dynamics and protein trafficking offer insight into pathophysiology and potential therapeutic targets.

CMT3 / HMSN III (Déjerine–Sottas Disease)

• Definition:
  • CMT3 (Déjerine–Sottas disease) refers to a group of severe inherited or sporadic neuropathies with significant clinical and genetic heterogeneity.
• Clinical Concept:
  • Despite overlap with other forms of CMT, the term remains a useful clinical classification for severe, early-onset neuropathies.
• Genetics:
  • Associated with dominant or recessive mutations in genes like PMP22, MPZ, EGR2, GJB1, CNTNAP1, and PRX.

Pathological Features

• General Pathology:
  • Resembles CMT1 but more severe.
  • Marked reduction in myelinated fibres, particularly large-calibre fibres.
  • Well-formed onion bulbs, often with double basement membrane lamellae.
  • Hypomyelination evidenced by a higher axon-to-total fibre diameter ratio.
  • Interstitial collagen hypertrophy in some cases.
• Congenital Hypomyelinating Neuropathy:
  • Absence or marked thinning of myelin (amyelinic form).
  • Onion bulbs with Schwann cell cytoplasm but little or no myelin.
  • Proliferation of microfilaments and unstable myelin structures in some cases.

Clinical Features

1. Classic Déjerine–Sottas Phenotype:

   • Onset: Early, often in the first year of life.
   • Symptoms:
     • Hypotonia and slow motor development.
     • Delayed ambulation in 30–50% of cases.
     • Diffuse and profound weakness, often asymmetrical.
     • Proximal muscle involvement and ataxia.
   • Associated Features:
     • Prominent eyes, thickened/everted lips (PMP22 mutations).
     • Pupillary abnormalities, sometimes Argyll Robertson pupil.
   • Course:
     • Severe, with many patients unable to walk independently by adolescence.
     • Severely reduced nerve conduction velocities (<10 m/s).

2. Congenital Hypomyelinating Neuropathy:

   • Severe Form:
     • Resembles Werdnig–Hoffmann disease.
     • Hypotonia, paralysis, respiratory impairment, and swallowing difficulties.
     • Often lethal within months or years.
   • Milder Form:
     • Survival with severe motor impairment.
     • Sensory deficits may develop later.

3. Genetic and Syndromic Associations:

   • SOX10 mutations: Associated with Hirschsprung disease.
   • GJA12 mutations: Linked to autosomal recessive Pelizaeus–Merzbacher-like disease.
   • CNTNAP1 mutations: Cause arthrogryposis multiplex congenita or Déjerine–Sottas phenotype without arthrogryposis.

Dominant Intermediate CMT (CMTDI)

• Definition:
  • Subtype of CMT with motor conduction velocities in the intermediate range (25–45 m/s) and dominant inheritance.
• Genetic Causes:
  • DNM2 (Dynamin 2) mutations:
    • Onset from early childhood to fifth decade.
    • May involve ptosis, ophthalmoplegia, cataracts.
  • INF2 (Inverted Formin 2) mutations:
    • Associated with glomerulosclerosis and renal failure.
• Clinical Features:
  • Conduction velocities overlap with CMT1 and CMT2 in different family members.
  • Rapid progression in some cases, leading to wheelchair dependence.

Diagnostic Insights

• Electrophysiology:
  • Severely reduced nerve conduction velocities (<10 m/s) or unmeasurable.
• Genetic Testing:
  • Testing for known mutations in genes associated with CMT3 and related syndromes.
• Histopathology:
  • Nerve biopsies reveal characteristic onion bulbs, hypomyelination, and Schwann cell abnormalities.

References

Menezes, M., & Ouvrier, R. (2018). Disorders of the peripheral nerves. In S. Blum, W. Dobyns, & W. Shields (Eds.), Aicardi’s Diseases of the Nervous System in Childhood (4th ed., pp.1236-1247). Mac Keith Press.